Varicella zoster virus (VZV) is a ubiquitous human herpesvirus and is the infectious agent of chickenpox (varicella) and shingles (zoster). Both varicella and, particularly, zoster continue to be health problems. A vaccine is in widespread use in children and may be used in the future in older adults, but we still do not know much about the pathogenesis of VZV infections (e.g. we do not understand the basis for attenuation of the vaccine virus). The study of VZV has been hampered by its human host range and its poor growth in cell culture. During the last granting period, we formed a consortium to develop a SCIDhu mouse model for the study of VZV pathogenesis in human fetal skin and thymus/liver implants. In this model, the pathology of infections appears authentic, the virus produced resembles that from actual human lesions and the vaccine virus is attenuated. We produced a series of VZV mutants and discovered several virulence determinants for the virus. In this proposal we will capitalize on our success with this model and extend it to allow study of human neural tissues. We will also study, in detail, two viral proteins - IE62 and the ORF47 protein kinase; the first of these is a (the) major viral gene regulatory protein and the second an indispensable (in SCIDhus) viral protein. Both in vitro and in vivo approaches will be taken and we will generate a new series of VZV mutants. In a new final aim, we will explore the structure of VZV particles, using the authentic material derived from SCIDhu growth. Understanding VZV pathogenesis will be the guide to designing "second generation" VZV vaccines.